The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and/or their active metabolites sufficient to provide a therapeutic effect.
Barbituric acid and its derivatives have been known since the turn of the century to possess pharmacological properties and some of them serve as active ingredients in widely used drugs. Barbituric acid derivatives are known to act mainly as sedatives, hypnotics and anaesthetics. Certain derivatives also have an anticonvulsive effect and are therefore employed in the treatment of epilepsy. Thus, pharmaceutical compositions containing 5-ethyl-5-phenyl barbituric acid (phenobarbital) are at present most widely used as drugs employed in the treatment of epilepsy. However, like other barbituric acid derivatives, phenobarbital has sedative and hypnotic effects, which are a disadvantage in the treatment of epilepsy. Therefore, a great effort has been devoted to the search for compounds which have anticonvulsant properties and at the same time are devoid of sedative and hypnotic effects.
For example, a known derivative of barbituric acid is 5,5-diphenyl barbituric acid, which was disclosed by S. M. McElvain in J. Am. Chem. Soc. 57, 1303 (1935), which is incorporated herein by reference in its entirety. The compound was found to be effective only in very large doses and therefore no pharmacological application was suggested. Raines et al. reported in Epilepsia 20, 105 (1979), which is incorporated herein by reference in its entirety, that 5,5-diphenyl barbituric acid has an anticonvulsant effect on rodents but with the disadvantage of relatively short term activity. Additionally non-sedating barbituric acid derivatives have been disclosed in Levitt, U.S. Pat. No. 4,628,056, and Moros et al., WO 02/007729 A1, published Jan. 31, 2002, each of which is incorporated by reference herein in its entirety.
Ischemia (stroke) is the third leading cause of death in the United States. When blood supply to the brain is reduced below a critical threshold, a cascade of biochemical events leads to irreversible damage to neurons and brain infarction. Research on treatment and prevention of ischemia is extensive but unfortunately it remains at a basic stage and no adequate therapies are yet in practice (Stroke Therapy: Basic clinical and pre-clinical directions, Leonard P. Miller, ed. (Wiley 1999)).
Barbiturates in high concentrations have been shown to be neuroprotective in cerebral ischemia in rodents and primates, to reduce the extent of ischemia brain infarction, and to prevent or lessen brain damage (Hoff J T, Smith A L, Hankinson H L, Nielsen S L, Stroke 1975, 6:28-33; Levy D E, Brierley J B. Delayed pentobarbital administration limits ischemia brain damage in gerbils; Lightfoote W E II, Molinari G F, Chase T N, Stroke 1977, 8:627-628; Corkill G, Chikovani O K, McLeish I, McDonald L W, Youmans J R, Surg. Neurol. 1976, 147-149). One theory as to how barbiturates prevent neuronal injury in ischemia is that they inhibit the ischemia-induced uncontrolled release of neurotransmitters, which can attain high, neurotoxic concentrations that cause neuronal death (Bhardwaj A, Brannan T, Weinberger J, J Neural Transom 1990, 82:111-117).
The literature regarding the neuroprotective effects of anesthetic barbiturates is over two decades old, but the clinical use of barbiturates has been severely limited because of toxicity. The dosages and blood and brain levels necessary to confer neuroprotection are toxic and cause lethargy, stupor, and coma. Even higher doses that might be more effective are lethal (Hoff J T, Smith A L, Hankinson H L, Nielsen S L, Stroke 1975, 6:28-33; Levy D E, Brierley J B. Delayed pentobarbital administration limits ischemia brain damage in gerbils; Lightfoote W E II, Molinari G F, Chase T N, Stroke 1977, 8:627-628; Corkill G, Chikovani O K, McLeish I, McDonald L W, Youmans J R, Surg. Neurol. 1976, 147-149; Masuda Y, Utsui Y, Shiraishi Y, Karasawa T, Yoshida K, Shimizu M., Epilepsia 1979, 20:623-633.), making barbiturates unsuitable for treatment of ischemia (Hoff J T, Smith A L, Hankinson H L, Nielsen S L, Stroke 1975, 6:28-33). These toxic side effects establish a “functional ceiling” on dosage for barbiturates, and have discouraged further research into the use of anesthetic/sedative barbiturates to protect from ischemia.
Levitt et al., U.S. Pat. No. 4,628,056 describes non-sedating oxopyrimidine derivatives and their use as anticonvulsants, anti-anxiety and muscle relaxant agents. The literature does not suggest the use of such compounds as neuroprotectant agents. Indeed, even in published studies about using sedative barbiturates for neuroprotection there is no reference to non-sedating barbiturate compounds. It is generally believed that the anticonvulsant and neuroprotective effects of barbiturates are linked to their sedative/hypnotic effects. For example, Lightfoote et al. suggested that the protective effects of pentobarbital are due to the duration of the barbiturate-induced anesthesia (Lightfoote W E II, Molinari G F, Chase T N, Stroke 1977, 8:627-628). This viewpoint has been reinforced by biochemical studies at the cell receptor level that relate all these effects to action at the GABA receptor. Thus, the prior art teaches away from using sedative barbiturates for neuroprotection because of their toxicity, and also teaches away from using non-sedative barbiturates as neuroprotectants because they lack sedating or anesthetic properties.
Some barbituric acid derivatives of Formula I and their methods of preparation are known. For example, U.S. Pat. No. 6,093,820, which is incorporated by reference herein in its entirety, describes the synthesis of N,N-bismethoxymethyl-5,5-dipheyl barbitutric acid (Formula I, R1═R2═CH2OMe and R3═R4═Ph). U.S. Pat. No. 4,628,056, which is incorporated by reference herein in its entirety, describes an alternative synthesis of this compound.